1. Field of the Invention
The present invention relates to diethylenetriamine pentaacetic acid (DTPA) derivates and metal complexes thereof, and radiation sources and contrast agents including the metal complexes. More particularly, the present invention relates to DTPA derivatives, which contain iodine and are useful as contrast agents for diagnosing renal function, metal complexes of the DTPA derivatives comprising 99mTc, 166Ho, 111In, 90Y, 153Sm, 186Re, 188Re, 68Ga, or 177Lu, which are useful as liquid radiation sources for treating vascular stenosis and contrast agents for diagnosing renal function, and radiation sources and contrast agents including the metal complexes.
2. Description of the Prior Art
Stenosis is the narrowing of blood vessels, and can occur in any area of the body, in which blood vessels are present, such as the cerebral vessels, cardiac vessels, peripheral vessels, and carotid arteries, due to fatty deposits, external stressors, hypertension, and the like. The use of liquid radiation sources for treating such vascular stenosis has the advantages of being cost-effective and of permitting the direct delivery of the uniform distribution of radiation to a site to be treated (Das T, Banerjee S, Samuel G, et al. [186/188Re] rhenium-ethylene dicysteine (Re-EC): preparation and evaluation for possible use in endovascular brachytherapy. Nucl Med Biol 2000, 27:189-97; Joh C W, Park C H, Kang H J, et al. Measurement of radiation absorbed dose in endovascular Ho-166 brachytherapy using a balloon angiocatheter. Nucl Med Comm 2000, 21:959-64; Kim H S, Cho Y H, Kim J S, et al. Effect of transcatheter endovascular radiation with holmium-166 on neointimal formation after balloon injury in porcine coronary artery. J Am Coll Cardiol 1998, 31(supplA):277A).
Such therapy with liquid radiation sources, however, has the risk of balloon rupture, which is an unlikely event, but which leads to leakage of radioactive materials into the blood stream.
In order to prevent a patient from being overexposed to radiation in the event of balloon rupture, a variety of complexes of radioisotopes and chelating agents, which are not retained in the organs or the body but are rapidly excreted via the kidneys, have been developed. In the event of balloon rupture leading to radiation leakage, radiation sources for endovascular radiation brachytherapy for stenosis must have high in vivo stability and be retained in a minimum dose in major organs, and as well, they must be rapidly and completely excreted from the body via the kidneys.
Certain complexes of Re-188 with chelating agents, which include 188Re-DTPA, 188Re-MAG3 (mercaptoacetylglycine3) and 188Re-EC (ethylene dicysteine), have been developed. In such complex forms, Re-188 is observed to be rapidly excreted in urine (Knapp F F, Guhlke S, Beets A L, et al. Intraarterial irradiation with rhenium-188 for inhibition of restenosis after PTCA-Strategy and evaluation of species for rapid urinary excretion. J Nucl Med 1997, 38:124; Majali M A. Studies on the preparation of Re-188-DTPA complexes using low specific activity Re-186 for antibody labeling. J Radianal Nucl Chem 1993, 170:471; Lee J, Lee D S, Kim K M, et al. Dosimetry of rhenium-188 diethylene triamine penta-cetic acid for endovascular intra-balloon brachytherapy after coronary angioplasty. Eur J Nucl Med 2000, 27:76-82; Lin W Y, Tsai S C, Hsieh B T, et al. Wang Evaluation of three rhenium-188 candidates for intravascular radiation therapy with liquid-filled balloons to prevent restenosis. J Nucl Cardiol 2000, 7:37-42; Das T, Banerjee S, Samuel G, et al. [186/188Re] rhenium-ethylene dicysteine (Re-EC): preparation and evaluation for possible use in endovascular brachytherapy. Nucl Med Biol 2000, 27:189-97).
Ho-166, which has radiochemical properties similar to those of Re-188, is advantageous in that its biodistribution can be readily imaged using a gamma camera because it emits both a maximum 1.85 MeV beta-ray and an 81 keV gamma-ray. Compared to Re-188, Ho-166 has the main advantage of being produced in the form of having high specific radioactivity at a high yield from naturally occurring Ho-165, making up 100% of the holmium on earth, through a nuclear reaction using a small-sized atomic reactor (Hong Y D, Park K B, Jang B S, et al. Holmium-166-DTPA as a liquid source for Endovascular brachytherapy. Nucl Med Biol 2002, 29:833-9; Majali M A, Saxena S K, Joshi S H, et al. Potential 166Ho radiopharmaceuticals for endovascular radionuclide therapy. II. Preparation and evaluation of 166Ho-DTPA. Nucl Med Comm 2001, 22:97-103).
Liquid radiation sources developed so far using Ho-166 include 166Ho-DTPA, 166Ho-DMDTPA (dimethyl diethylenetriaminepentaacetic acid), 166Ho-DOTA (1,4,7,10-tetraazadodecane-N,N′,N″,N′″-tetraacetic acid) and 166Ho-EC (Joh C W, Park C H, Kang H J, et al. Measurement of radiation absorbed dose in endovascular Ho-166 brachytherapy using a balloon angiocatheter. Nucl Med Comm 2000, 21:959-64; Majali M A, Mita, Debnath C, Saxena S K, Sangeeta H. Joshi Preparation and evaluation of [166Ho] holmium-dimethyl diethylenetriaminepentaacetic acid (DMDTPA) as potential radiopharmaceutical for endovascular radiation therapy (EVRT). Appl Rad Isotopes 2004, 56:863-9; Das T, Chakraborty S, Banerjee S. Preparation and animal biodistribution of 166Ho labeled DOTA for possible use in intravascular radiation therapy (IVRT). J Label Compd Radiopharm 2003, 46:197-209; Chakraborty S, Unni P R, Banerjee S, et al. Potential 166Ho radiopharmaceuticals for intravascular radiation therapy (IVRT)-I: 166Ho labeled ethylene dicysteine. Nucl Med Biol 2001, 28:309-17).
The liquid radiation source 166Ho-DTPA is prepared through a simple procedure of mixing holmium and DTAP at pH 2-8 immediately before use. This simple procedure results in the formation of complexes having a high radiochemical purity greater than 98% (Hong Y D, Park K B, Jang B S, et al. Holmium-166-DTPA as a liquid source for Endovascular brachytherapy. Nucl Med Biol 2002, 29:833-9; Korean Pat. Registration No. 361091).
Upon angioplasty for treating cardiac vascular diseases with liquid radiation sources, which is commonly performed with computed tomography (CT) and angiography, the use of CT contrast agents, such as Hexabrix (320), Imeron (350) and Visipaque (320), permits the visual observation of the balloon interior to determine the presence of bubbles, which interrupt the precise delivery of a radiation dose to a site of cardiac vessels where stenosis occurs, and to determine whether the balloon is accurately positioned at a site to be treated so as to have a proper shape (Hong Y D, Choi S J, Choi S M, Jang B S. The availability of contrast media in the application of Holmium-166-DTPA for vascular brachytherapy. Nucl Med Biol 2004, 31:225-30).
However, when contrast agents are used as diluents, they have side effects including the formation of unknown complexes through a reaction with Ho-166, resulting in delayed or almost no excretion of the radionuclide from the body.
In addition, radiation imaging involves identifying specific pathological conditions or evaluating the severity of symptoms by injecting a contrast agent containing a radioisotope into the body and detecting the biodistribution of the contrast agent. Radionuclides, for use in the preparation of contrast agents in which a chelating agent is coordinate-bonded to a radionuclide, must satisfy the requirements of maximizing detection efficiency and minimizing a radiation dose absorbed by a patient. Thus, radionuclides emitting gamma radiation and having physical half-lives shorter than the imaging time are useful. 99mTc (99m-technetium) is commonly used.
The diagnosis of renal diseases using 99mTc is performed with dimercaptosuccinic acid (DMSA) for obtaining anatomical imaging and with GHA, DTPA, MAG3 and EC for evaluating renal function (Technetium Radiopharmaceuticals. In: Owunwanne A, Patel M, Sadek S., The handbook of Radiopharmaceuticals. Chapman & Hall Medical 1995, 57-105).
In particular, the renal function is evaluated by assessing the excretion pattern of a radionuclide for a predetermined period of time using a gamma camera in order to obtain a renogram curve representing renal function. The use of complexes displaying rapid excretion patterns enhances detection efficiency and reduces detection time, thereby providing an economic benefit and ensuring accurate diagnosis.
Iodine compounds, including diatrizoate, ioxaglate, iohexol, and iodixanol, have been used as X-ray contrast agents. Metals, including gadolinium (Gd), tungsten (W), and lead (Pb), have been also used in the form of metal complexes. Imaging of these contrast agents is achieved using a computed tomography (CT) or angiography camera (Yu S B, Watson A D. Metal-Based X-ray Contrast Media. Chem. Rev. 1999, 99:2353-78).
Metal complexes of DTPA or DOTA with, for example, gadolinium (Gd), dysprosium (Dy), and manganese (Mn) are useful as contrast agents for magnetic resonance (MR) imaging (Caravan P, Ellison J J, McMurry T J, Lauffer R B. Gadolinium (III) Chelates as MRI Contrast Agents: Structure, Dynamics, and Applications. Chem. Rev. 1999, 99:2293-352).
At present, with the recent advances in imaging equipment, such as MR imaging, CT, angiography, CT/SPECT, and CT/PET, and the development and practical use of hybrid imaging equipment, there is a need for the development of complex compounds capable of accomplishing two or more purposes at one time.
In particular, there is a need for the development of contrast agents enabling real-time imaging upon angioplasty. In this regard, taking into account the fact that some DTPA derivatives easily react with radioisotopes, such as Re-188 and Ho-166, to form complexes, which can be used as liquid radiation sources in balloon angioplasty of vascular stenosis, and contain iodine, which is useful as a contrast agent for X-ray imaging, the present inventors synthesized complex compounds, which are useful as radiation sources for treating vascular stenosis and contrast agents, by binding DTPA derivatives and radioisotopes, thereby leading to the present invention.
The DTPA derivatives of the present invention may form complexes with gamma-emitting radionuclides, such as Tc-99m and In-111, which are quickly excreted in the urine, in order to minimize the patient's exposure to radiation, which is an unlikely event. Such complexes are useful as diagnostic agents for renal function because the radionuclides used can be imaged using a gamma camera. Also, the DTPA derivatives may be directly bound to gadolinium (Gd) so as to be used as contrast agents for MR imaging.